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Rapid Elaboration of Fragments into Leads by X-ray Crystallographic Screening of Parallel Chemical Libraries (REFiLX)

Journal Article


Abstract


  • A bottleneck in fragment-based lead development is the lack of systematic approaches to elaborate the initial fragment hits, which usually bind with low affinity to their target. Herein, we describe an analysis using X-ray crystallography of a diverse library of compounds prepared using microscale parallel synthesis. This approach yielded an 8-fold increase in affinity and detailed structural information for the resulting complex, providing an efficient and broadly applicable approach to early fragment development.

UOW Authors


  •   Bentley, Matthew (external author)
  •   Ilyichova, Olga (external author)
  •   Wang, Geqing (external author)
  •   Williams, Martin (external author)
  •   Sharma, Gaurav (external author)
  •   Alwan, Wesam (external author)
  •   Whitehouse, Rebecca (external author)
  •   Mohanty, Biswaranjan (external author)
  •   Scammells, Peter (external author)
  •   Heras, Begona (external author)
  •   Martin, Jennifer
  •   Totsika, Makrina (external author)
  •   Capuano, Ben (external author)
  •   Doak, Bradley (external author)
  •   Scanlon, Martin (external author)

Publication Date


  • 2020

Citation


  • Bentley, M., Ilyichova, O., Wang, G., Williams, M., Sharma, G., Alwan, W., Whitehouse, R., Mohanty, B., Scammells, P., Heras, B., Martin, J., Totsika, M., Capuano, B., Doak, B. & Scanlon, M. (2020). Rapid Elaboration of Fragments into Leads by X-ray Crystallographic Screening of Parallel Chemical Libraries (REFiLX). Journal of medicinal chemistry, 63 (13), 6863-6875.

Scopus Eid


  • 2-s2.0-85088208086

Ro Metadata Url


  • http://ro.uow.edu.au/dvcripapers/6

Number Of Pages


  • 12

Start Page


  • 6863

End Page


  • 6875

Volume


  • 63

Issue


  • 13

Place Of Publication


  • United States

Abstract


  • A bottleneck in fragment-based lead development is the lack of systematic approaches to elaborate the initial fragment hits, which usually bind with low affinity to their target. Herein, we describe an analysis using X-ray crystallography of a diverse library of compounds prepared using microscale parallel synthesis. This approach yielded an 8-fold increase in affinity and detailed structural information for the resulting complex, providing an efficient and broadly applicable approach to early fragment development.

UOW Authors


  •   Bentley, Matthew (external author)
  •   Ilyichova, Olga (external author)
  •   Wang, Geqing (external author)
  •   Williams, Martin (external author)
  •   Sharma, Gaurav (external author)
  •   Alwan, Wesam (external author)
  •   Whitehouse, Rebecca (external author)
  •   Mohanty, Biswaranjan (external author)
  •   Scammells, Peter (external author)
  •   Heras, Begona (external author)
  •   Martin, Jennifer
  •   Totsika, Makrina (external author)
  •   Capuano, Ben (external author)
  •   Doak, Bradley (external author)
  •   Scanlon, Martin (external author)

Publication Date


  • 2020

Citation


  • Bentley, M., Ilyichova, O., Wang, G., Williams, M., Sharma, G., Alwan, W., Whitehouse, R., Mohanty, B., Scammells, P., Heras, B., Martin, J., Totsika, M., Capuano, B., Doak, B. & Scanlon, M. (2020). Rapid Elaboration of Fragments into Leads by X-ray Crystallographic Screening of Parallel Chemical Libraries (REFiLX). Journal of medicinal chemistry, 63 (13), 6863-6875.

Scopus Eid


  • 2-s2.0-85088208086

Ro Metadata Url


  • http://ro.uow.edu.au/dvcripapers/6

Number Of Pages


  • 12

Start Page


  • 6863

End Page


  • 6875

Volume


  • 63

Issue


  • 13

Place Of Publication


  • United States